A New Type of CB1 Blocker Reduced Both Nicotine and Cannabis Seeking in Monkeys
A CB1 receptor neutral antagonist reduced nicotine and THC self-administration and relapse in monkeys with fewer expected side effects than rimonabant, pointing to a potential dual-addiction treatment.
Quick Facts
What This Study Found
Researchers compared two types of CB1 receptor blockers in squirrel monkeys: rimonabant (an inverse agonist that was withdrawn from the market due to psychiatric side effects) and AM4113 (a newer neutral antagonist).
Both compounds reduced nicotine and THC self-administration and prevented relapse triggered by drug cues or priming doses. Neither compound affected cocaine or food-motivated behavior, demonstrating selectivity for cannabinoid and nicotine reward.
However, both rimonabant and AM4113 did reduce cue-induced relapse for cocaine, suggesting endocannabinoid involvement in how drug-associated cues trigger craving across different drugs.
The key clinical implication is that neutral antagonists like AM4113 may provide the addiction-reducing benefits of rimonabant without the depression and anxiety side effects that led to rimonabant's withdrawal from the market.
Key Numbers
Both rimonabant and AM4113 reduced nicotine and THC self-administration. Neither affected cocaine or food reinforcement. Both reduced cue-induced reinstatement across all drug types. AM4113 is expected to have fewer psychiatric side effects than rimonabant.
How They Did This
Squirrel monkey study using intravenous self-administration paradigms for nicotine, THC, and cocaine. Researchers measured maintenance of drug-taking behavior and reinstatement of drug-seeking after extinction (modeling relapse). Both rimonabant and AM4113 were tested against each drug and food reinforcement.
Why This Research Matters
Tobacco and cannabis are the two most commonly used addictive substances worldwide. A single medication that could reduce both addictions simultaneously would be enormously valuable. Rimonabant showed this potential but was too dangerous. Neutral antagonists may preserve the benefit while eliminating the psychiatric risk.
The Bigger Picture
The failure of rimonabant was a major setback for cannabinoid-based addiction medicine. This study reignites the approach by showing that a mechanistically different type of CB1 blocker (neutral antagonist vs inverse agonist) can achieve the same anti-addiction effects. The finding that cue-induced relapse involves endocannabinoid signaling across different drugs suggests the endocannabinoid system plays a broad role in how environmental triggers drive drug seeking.
What This Study Doesn't Tell Us
Primate self-administration studies have good translational value but are not human clinical trials. AM4113 has not been tested in humans. The assumption that neutral antagonists will have fewer psychiatric side effects than inverse agonists has not been clinically confirmed. The sample size was small (typical for primate studies).
Questions This Raises
- ?Will AM4113 or similar neutral antagonists be safe in human clinical trials?
- ?Could these compounds help with other addictions beyond tobacco and cannabis?
- ?Is the absence of food-reinforcement effects maintained at all doses, ensuring the compound would not cause appetite loss?
Trust & Context
- Key Stat:
- New CB1 neutral antagonist matched rimonabant's anti-addiction effects for both nicotine and THC without affecting food reward.
- Evidence Grade:
- Moderate evidence from controlled primate studies using validated self-administration paradigms, with strong translational relevance but no human data yet.
- Study Age:
- Published in 2016. Development of CB1 neutral antagonists for addiction treatment continues in preclinical stages.
- Original Title:
- Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.
- Published In:
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(9), 2283-93 (2016)
- Authors:
- Schindler, Charles W(4), Redhi, Godfrey H(2), Vemuri, Kiran(7), Makriyannis, Alexandros, Le Foll, Bernard, Bergman, Jack, Goldberg, Steven R, Justinova, Zuzana
- Database ID:
- RTHC-01259
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Why was rimonabant taken off the market?
Rimonabant, a CB1 receptor inverse agonist, effectively reduced appetite and addictive behaviors but caused serious psychiatric side effects including depression and suicidal thoughts. It was withdrawn from European markets in 2008 and never approved in the US.
How is a neutral antagonist different?
An inverse agonist like rimonabant not only blocks the receptor but pushes its activity below baseline, which may cause the psychiatric side effects. A neutral antagonist simply blocks the receptor without pushing activity in either direction, potentially preserving the therapeutic benefits without the psychiatric risks.
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Cite This Study
https://rethinkthc.com/research/RTHC-01259APA
Schindler, Charles W; Redhi, Godfrey H; Vemuri, Kiran; Makriyannis, Alexandros; Le Foll, Bernard; Bergman, Jack; Goldberg, Steven R; Justinova, Zuzana. (2016). Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(9), 2283-93. https://doi.org/10.1038/npp.2016.27
MLA
Schindler, Charles W, et al. "Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.." Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2016. https://doi.org/10.1038/npp.2016.27
RethinkTHC
RethinkTHC Research Database. "Blockade of Nicotine and Cannabinoid Reinforcement and Relap..." RTHC-01259. Retrieved from https://rethinkthc.com/research/schindler-2016-blockade-of-nicotine-and
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.